Both the number of candidates in development and those receiving approvals are rising at an accelerated pace. As the portfolio of commercially available biosimilars expands, the need for effective pharmacovigilance (PV) capabilities is growing as well. Providers of PV services must be highly knowledgeable about both the regulatory requirements and the specific reference product(s) for the biosimilars they support. With a proven track record, PrimeVigilance leads the way with expert-driven, state-of-the-art solutions, delivering tailored, cost-effective pharmacovigilance services that address both regulatory complexities and specific product needs.
Pharmacovigilance in the Biosimilars Boom: Adapting to a Growing Market
While the adoption of biosimilars was initially tardy, recent years have seen a surge in their acceptance, with an increasing number of candidates being developed and approved. The biosimilars market is projected to expand at a compound annual growth rate of approximately 18% over the next five (5) to ten (10) years.1–3 In the United States alone, despite extensive patent litigation, 38 out of 49 biosimilars approved by the U.S. Food and Drug Administration (FDA) had been launched as of March 2023.1
This growth is fueled by several factors: patent expirations, global governmental efforts to enhance healthcare access and equity, and the cost advantages biosimilars offer over reference biologics. Notably, the acceptance of biosimilars is not confined to developed economies; emerging markets are increasingly embracing these alternatives, particularly for managing chronic diseases that are on the rise globally.
As the portfolio of commercially available biosimilars expands, the demand for robust pharmacovigilance (PV) systems intensifies. Unlike small chemically synthesized generic molecules, biosimilars, large molecules with far more complex structures, are not exact copies of their reference products. Like all biologics, they can vary from batch to batch owing to their production in living cells. This necessitates stringent PV regulatory frameworks, akin to those required for the originator biologics. Each biosimilar must undergo tailored post-marketing studies to verify its quality, safety, and efficacy independently of its reference product.
Effective PV also demands meticulous coordination and communication between safety and quality control departments within companies or among these departments and external PV service providers. Managing product quality complaints / adverse event reporting requires traceability down to the specific lot number. In turn, the overall process requires strong communication between these departments to ensure appropriate data collection and effective messaging to the patients and/or healthcare professionals.
Furthermore, robust organization of data collection during post-marketing phases is essential, not only for safety and product quality data related to the biosimilar itself but also for ensuring the correct use of associated medical devices, which quite often come as integral parts of the product (e.g., pen dispensers for self-administration). Organized data collection, for example through patient support programs, not only simplifies the process but also enhances the quality of the data gathered, surpassing what is typically achieved through spontaneous reporting.
Given the specific setting in a safety environment, PV providers must possess deep knowledge of both the regulatory landscape and the specific reference products related to the biosimilars they support, ensuring they can navigate the unique challenges posed by each product effectively.
Balancing Cost and Quality in Biosimilar Development
Biosimilars offer a significant cost advantage compared with branded biologics, which naturally leads developers to be highly cost-conscious. However, despite the focus on affordability, the complexity of biosimilar development —— far surpassing that of small molecule generics —— necessitates extensive, robust, and preferably solicited data collection to establish a safety and efficacy profile comparable to that of the reference biologic. Thus, maintaining high quality standards remains paramount.
Since their introduction to the market —— 2006 in Europe and 2016 in the United States —— biosimilars are relatively new compared with generics, which have been around for over half a century. This novelty underscores the critical need for robust PV programs to ensure patient safety, particularly as biosimilars begin to occupy more significant market shares.
PV service providers play a crucial role in this landscape. They must operate with high efficiency and strict adherence to budget constraints yet without compromising on the thoroughness required to meet stringent regulatory standards. This ensures the safety of biosimilar products remains uncompromised, despite financial considerations.
The dual imperative of ensuring the highest quality and regulatory compliance in biosimilar development and postmarketing surveillance while simultaneously controlling costs presents a unique challenge: developers must navigate the tightrope of uncompromised safety and financial prudence, leveraging innovative PV strategies and technologies to maintain the balance.
Benefit–Risk Critical Assessments in the Biosimilar Life Cycle
In PV, conducting ongoing benefit–risk assessments for medicinal products is a cornerstone activity. This assessment, crucially tailored to the specific molecule, extends beyond the biosimilar itself to encompass the reference product and its spectrum of approved indications —— even those for which the biosimilar has not received approval. Additionally, comparative data from other biosimilars of the same reference product are also considered, drawing from a wide array of sources, including scientific literature, regulatory publications, and institutional reports, to form a comprehensive benefit–risk analysis.
The evaluation of benefit versus risk for biosimilars considers more factors in addition to standard PV data revised during the assessment: the manufacturing process, the supply chain supporting the product, overall product quality, and variances such as those from batch to batch. The selection of data for these assessments is critical; with acceptable quality variances defined, it is essential to choose data judiciously to ensure a reliable assessment. Collaboration with a PV provider who possesses a thorough understanding of both the biosimilar and its reference, along with the relevant regulatory landscapes, is pivotal. Such partnerships are instrumental in conducting precise and contextually appropriate benefit–risk analyses, ensuring that safety decisions are informed by comprehensive and meticulously vetted data.
Strategic Indication Extrapolation for Biosimilars
Biosimilars may receive marketing authorizations for some —— but not necessarily all —— of the indications approved for their reference products. Often, a biosimilar is granted what is known as indication extrapolation. This allows it to be approved for additional uses beyond the initial indication without undergoing extensive new clinical trials. Such decisions are generally supported by robust data on the biosimilar's stability, pharmacodynamics, and other critical safety findings.
The practice of indication extrapolation underscores the necessity for a meticulously tailored PV program. A well-structured program is crucial for collecting the necessary data to convincingly demonstrate that a biosimilar is safe and effective for expanded indications. This data must rigorously confirm that the biosimilar's performance matches that of the reference product across various therapeutic uses, ensuring patient safety and efficacy across all potential applications.
Interchangeability in Biosimilars: Opportunities and Patient Perspectives
Several blockbuster biologics losing patent protection are now facing competition from multiple biosimilars. For example, the branded drug aflibercept, which is indicated for age-related macular degeneration (AMD), macular edema, diabetic retinopathy, and other related conditions, competes with five (5) biosimilars in the United States. Notably, none of these biosimilars cater to the high-dose version of branded aflibercept, and not all are approved for the same indications.
The FDA has granted two (2) aflibercept biosimilars status as interchangeable biosimilars. This designation allows pharmacists (subject to state laws) to substitute these for the reference product without needing to consult the prescribing physician. Despite the possibility of switching between these treatments, there remains significant patient hesitancy. Patients are often reluctant to switch medications, particularly in chronic conditions, fearing the risks of ineffectiveness or adverse reactions associated with a new treatment. This hesitancy underscores the necessity for comprehensive education directed at both patients and healthcare providers to enhance understanding and confidence in biosimilar options. In the meantime, biosimilars are most successfully prescribed to newly diagnosed patients.
Addressing this concern, the FDA has carried out a systematic review and meta-analysis of safety data from patients who either switched between a reference product and a biosimilar or remained on one treatment.4 This analysis aimed to detect any significant differences in outcomes, such as mortality, serious adverse events, or discontinuations due to adverse reactions, including immunogenic responses. The findings revealed no significant differences, highlighting the potential for PV data to not only ensure regulatory compliance but also bolster educational initiatives to promote the safety and benefits of biosimilars, thereby facilitating more widespread acceptance and use.
Collaboration in Traceability: The Role of PV Providers
Traceability is a crucial element in the management of biologics, requiring the meticulous recording of lot or batch numbers and box identifiers. This information links each product to its specific manufacturing details, such as the site and date, which are vital in addressing any safety concerns that may arise. Traceability is also important when performing aggregate analyses from any perspective.
In clinical settings like hospitals, maintaining a detailed registry of these identifiers is generally feasible and effective. However, the process becomes significantly more complicated when biologics are administered at home by patients. The main challenge in such cases is ensuring that individuals responsible for tasks such as maintaining registries or managing patient support programs—often the patients themselves or their caregivers—are properly informed and diligent in accurately recording all necessary details. Cooperation with patient support groups is also essential to ensure consistent data collection, as the typical method involves or e-mail (in correspondence that is not connected), as well as a paper-based trail that often follows the product from distribution to the patient.
While the responsibility for establishing these traceability systems primarily rests with the drug manufacturer and marketing authorization holders, the role of a PV service provider is also pivotal. A competent PV provider collaborates closely with their client to implement robust traceability mechanisms that uphold the integrity of safety data and facilitate comprehensive aggregate analyses. This partnership is instrumental in creating a reliable framework that accommodates the complexities of tracking biologics, particularly those used outside traditional healthcare environments.
Expertise in Biosimilar PV Support at PrimeVigilance
For nearly 15 years, PrimeVigilance has specialized in providing PV support specifically tailored to the needs of biosimilar developers. Our longstanding relationships with many clients reflect our commitment to delivering efficient, effective, compliant and cost-conscious PV services that do not compromise on quality or safety. We operate as a seamless extension of each client's team, offering expert guidance on regulatory framework and data collection, including operationalization of very difficult activities to improve efficiency and cost-effectiveness.
At the core of our service is a bespoke approach: we tailor our support to the specific requirements of each biosimilar, drawing on the deep insights of our regulatory intelligence and scientific teams. These teams comprehensively gather data from regulators and other relevant institutions, clinical trials, other studies, and real-world evidence, focused on a specific client's therapy or portfolio. This targeted data collection is crucial for setting up and maintaining compliant PV systems that are robust and responsive to the unique challenges posed by biosimilars.
Moreover, PrimeVigilance is renowned for its capability to develop comprehensive risk management plans —— a critical component for biosimilar PV. Our success in this area, as in all others, is driven by our deep pool of knowledge, understanding, and sector-specific expertise.
Unlike larger contract research organizations where PV might be one of many divisions, PrimeVigilance is dedicated exclusively to PV. This focus enables us to provide a level of personalized, flexible support that is unparalleled in the industry. Our team, equipped with state-of-the-art tools and technologies, excels in crafting PV solutions that prioritize quality, efficiency, and meticulous data collection, setting us apart as leaders in the PV services.
References
1. Jeremias, Skylar. “Global Biosimilar Market Projected to Reach $1.3 Trillion by 2032.” Center for Biosimilars. 11 Apr. 2024. https://www.centerforbiosimilars.com/view/global-biosimilar-market-projected-to-reach-1-3-trillion-by-2032
2. Biosimilar Market Size, Share & Trends by Drug Class [Monoclonal Antibodies (Adalimumab Infliximab, Rituximab, Trastuzumab), Insulin, Erythropoietin, Anticoagulants], Indication, Region – Global Forecast to 2028. Markets and Markets. Jun. 2023. https://www.marketsandmarkets.com/Market-Reports/biosimilars-40.html
3. Biosimilars Market Size Poised to Hit USD 150.26 Billion by 2033. Nova One Advisor. 17 Jun. 2024. https://www.biospace.com/biosimilars-market-size-poised-to-hit-usd-150-26-billion-by-2033
4. Anderson, Leigh Ann. “Does Eylea have a biosimilar?” Drugs.com. 3 Sep. 2024. https://www.drugs.com/medical-answers/eylea-have-biosimilar-3577184/
5. “FDA, Switching Between Biosimilars and Their Reference Counterparts with Dr. Sarah Yim.” Q&A with FDA Podcast. 8 May 2024. https://www.fda.gov/drugs/news-events-human-drugs/switching-between-biosimilars-and-their-reference-counterparts-dr-sarah-yim
